Posted by Phillipa on March 14, 2011, at 21:16:33
From Medscape Medical News > Neurology
FDA Committee Backs Lamotrigine XR Monotherapy for Partial Seizures
Allison GandeyAuthors and Disclosures
March 11, 2011 A US Food and Drug Administration (FDA) committee has decided in a majority vote to support lamotrigine extended release as monotherapy for partial-onset seizures. An immediate-release formulation of the GlaxoSmithKline product sold under the brand name Lamictal is already available.Britt Anderson, MD, chair of the Peripheral and Central Nervous System Drugs Advisory Committee, was among the 10 members who voted in favor of the extended-release product. "I voted yes. The already approved immediate-release formulation was relevant to my decision but not critical," he said.
Dr. Britt AndersonTwo committee members voted against lamotrigine extended release, 1 member abstained, and 1 was absent. Those voting against this option voiced concern about the study design.
"The availability of lamotrigine immediate release was not sufficient to overcome my reservations," said David Treiman, MD, from Arizona State University in Phoenix.
At issue was the use of historical controls in the trial. Many neurologists consider placebo-controlled studies in patients with epilepsy unethical. In an effort to develop a practical trial design that might be able to provide interpretable data on the effectiveness of anticonvulsants as monotherapy, investigators developed an approach comparing a newly treated group with a historical control. This historical control was created from the control groups of previously performed monotherapy studies.
Dr. Jacqueline FrenchThe design is creative but fraught with challenges. Jacqueline French, MD, who was based at the University of Pennsylvania, Philadelphia, at the time this approach was developed, presented it at the meeting. She explained the new control group was based on the data from the control groups in 8 previously performed monotherapy studies. These studies were not identical but were of very similar design.
Each study enrolled patients whose seizures were not well controlled by at least 1 antiepileptic drug. The study drug was then added to the background drugs. The study drug was either a dose of an anticonvulsant thought to be effective or a dose thought to be not fully effective a so-called pseudoplacebo control.
During a varying period of several weeks, the background drugs were withdrawn, leaving patients either on the full dose of the new drug or the pseudoplacebo. Patients were then followed up until they met 1 of 4 escape criteria or completed the study. The proportions of patients who met escape criteria were then compared between the 2 groups.
Statisticians Take Aim
Dr. French fielded tough questions from committee members. They wanted to know if a placebo-controlled study is considered unethical, how would a pseudoplacebo of a known ineffective dose be considered ethical?
Also, might historical control data gathered in the past yield response data different from that in contemporary studies? And if all patients in the trial are aware they are receiving active medication, wouldn't this call into question the comparability of the responses seen in the new study to those seen in the historical control given the earlier patients might have been enrolled in blinded, placebo-controlled studies?
"My sense is there was a difference of opinion between the statisticians on the committee and the clinicians," Lily Jung Henson, MD, from the Swedish Neuroscience Institute Medical Center in Seattle, Washington, told Medscape Medical News. Dr. Jung Henson is consumer representative for the committee. "As a clinician myself, I feel we have to get antiepileptic drugs on the market, and I believe very strongly that placebo-controlled trials are unethical in patients with epilepsy who are not in a controlled environment."
Dr. Anderson encouraged committee members not to blame Dr. French for the study limitations that have ensued in the field.
Still, the committee acknowledged the studies are problematic. Dr. Anderson called historical-controlled trials "ethically problematic" but acknowledged they may be appropriate in a subset of patients, such as in pediatrics, when the efficacy of an antiepileptic drug as add-on therapy has already been established and there may be an opportunity for monotherapy.
"We will need to find new approaches moving forward," Dr. Jung Henson said during an interview. "I think the committee supported lamotrigine because it is a familiar drug and people feel comfortable with it. A brand new drug would have had a more difficult time on the basis of the data presented."
The FDA will review the committee's response and make its decision in the months to come. If approved, lamotrigine extended release could be available as monotherapy for patients 13 years and older with partial seizures who are already receiving therapy with a single antiepileptic drug.
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